The long term aim of this work is to define the loci and mechanisms of cytogenetic variation in somatic cells, including the relation of such changes to carcinogenesis. The role of cytoplasmic determinants as control systems will be examined in cultures of Chinese hamster and mouse cells. Variation at this level may result from genetic changes occurring in mitochondria or other cytoplasmic organelles. Alternatively, variation may involve cytoplasmic determinants that are epigenetic in function, and which serve to modulate the patterns of nuclear gene expression. A basis for examining both possibilities lies in the enucleation of cells with Cytochalasin B to yield cytoplasts which can be fused with nucleated indicator cells to give cytohybrids. Using drug resistant donor cells, tests will be made in this way for the cytoplasmic transfer of marker characteristics in the absence of a nuclear contribution. Alternatively, isolated mitochondria will be prepared to test for the direct transfer of drug resistance markers to indicator cells. In further studies, cytohybrids will be constructed between normal and neoplastic lines of mouse cells, in reciprocal combination. Derivative cell types will be inoculated into mice to investigate the effects of cytoplasmic determinants on the phenotypic expression of malignancy.